The overall objectives of this proposal are: 1) to elucidate the role of vascular injury in mediating ischemia-reperfusion induced loss of myocardial contractile function and myocardial infarction, 2) to assess the potential role of endothelial cells in modulating coronary vascular tone and responses to vasoactive agents, and to examine effects of diabetes on the susceptibility of the coronary vasculature to ischemic injury, and on responses of the diabetic vasculature to vasoactive drugs. The first objective will be addressed by assessing changes in vascular resistance, vascular permeation by I125-BSA, and myocardial contractile function in isolated-perfused rabbit hearts subjected to global no-flow ischemia or low-flow hypoxia followed by reperfusion under conditions of constant flow or constant pressure. The second objective will be investigated by selectively damaging endothelium by perfusing hearts with colloidal silica or with proteases or phospholipases covalently bound to 0.2-MuM microspheres (confined to the vascular lumen). The third objective will be accomplished by carrying out experiments identical to those for the first objective, and by additional experiments with vasoactive agents, using rabbits rendered diabetic by administration of alloxan. Vascular permeability changes will be monitored by use of residue-detection techniques which allow quantification of radiolabeled tracer-transport rates across endothelium, while myocardial contractile function will be monitored from a left ventricle balloon. Changes in vascular resistance in response to ischemia, vasoactive agents, and endothelial cell damage will be assessed physiologically by monitoring changes in vascular perfusion pressure and flow rate. Electron microscopy also will be used to assess vascular structural integrity. These studies should provide important information regarding: 1) effects of ischemia (and interactions between diabetes and ischemia) on coronary vascular structure and function, 2) the role of endothelial cell injury in the pathogenesis of vasospasm, and 3) the role of vascular injury and vasospasm in the pathogenesis of myocardial infarction.